Glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9670195-B2
Application number	US-201314424615-A
Country	US
Kind code	B2
Filing date	Aug 29, 2013
Priority date	Aug 31, 2012
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention provides compounds for inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.

First claim

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
R 1 is H;
R 2 is C 1-6 acyl;
R 3 is H and R 4 is OH, or R 3 is H and R 4 is F, or R 3 is F and R 4 is H, or R 3 is F and R 4 is F, or R 3 is OH and R 4 is H;
R 5 is selected from the group consisting of: CH 3 , CH 2 F, CHF 2 , and CH 2 OH; and
R 6 is selected from the group consisting of: C 2-10 alkenyl, C 2-10 alkynyl, C 8-20 arylalkyl, C 8-20 arylalkenyl, and C 8-20 arylalkynyl each optionally substituted from one to four substituents with one of more of halo, OH, OCF 3 , CN, SO 2 NH 2 , SO 2 Me, C(O)NH 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CF 3 , CH 2 CH 2 CH 2 F, C 1-6 alkyl, C 1-6 alkoxy, or C 3-7 cycloalkyl.

2. The compound of claim 1 wherein the compound is selected from the following group:
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)acetamide;
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4S,5S)-4-fluoro-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-4-fluoro-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5R)-5-(fluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5R)-5-(difluoromethyl)-4-hydroxy-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-4-hydroxy-5-methyl-1-(3-phenylpropyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-((Z)-5,5,5-trifluoropent-3-en-1-yl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(pent-4-yn-1-yl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-1-cinnamyl-4-hydroxy-5-(hydroxymethyl)pyrrolidin-3-yl)propionamide;
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylprop-2-yn-1-yl)pyrrolidin-3-yl)propionamide;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

4. The compound of claim 1 wherein the compound is
N-((3S,4R,5S)-4-hydroxy-5-(hydroxymethyl)-1-(3-phenylpropyl)pyrrolidin-3-yl)acetamide or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

Assignees

• Alectos Therapeutics Inc
• Merck Sharp & Dohme

Inventors

• Mceachern Ernest J
• Sun Jianyu
• Vocadlo David J
• Zhou Yuanxi
• Selnick Harold G

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D401/08

  linked by a carbon chain containing alicyclic rings · CPC title